To date, no vaccine to prevent Staphylococcus aureus infection has succeeded in Phase III clinical trials. Meanwhile, the need for a vaccine continues to escalate as does the ability of this pathogen to acquire antibiotic resistance. Our goal is to demonstrate the effectiveness of virus-like particles (VLPs) as an innovative broad- spectrum platform for production of vaccines against S. aureus secreted virulence factors. VLPs are a novel approach to the design of vaccines targeting bacterial infection and the ability of VLP-based vaccines targeting secreted S. aureus toxins to induce a protective immune response has not been investigated. Therefore, the goal of this proposal is to test the hypothesis that presentation of toxin peptides on VLPs can be used to induce adaptive immunity targeting major S. aureus secreted virulence factors. To test this hypothesis we will pursue the following specific aims: Specific Aim #1: To determine the immunogenicity and efficacy of VLPs displaying structurally selected Hla and bi-component leukotoxin peptides in nave and S. aureus colonized mice. Specific Aim #2: To determine the immunogenicity and efficacy of VLPs displaying 10-mer peptides representing the toxin peptidome of Hla and bi-component leukotoxins in nave and S. aureus colonized mice. Importantly, unlike other platforms and experimental adjuvants, VLPs are currently used in FDA-approved vaccines (like the current HPV vaccines). Therefore, if experimental approaches using VLPs are confirmed in animal models, they can potentially translate into human trials fairly readily.